Summary: Globally, the vast majority of HIV infections occur as a result of vaginal transmission. In the absence of an effective vaccine, novel HIV prevention strategies are desperately needed. Systemic use of current antiretroviral treatments is expensive and potentially toxic to recommend for uninfected persons as prevention, and may result in emergence of resistant HIV strains. However, coitally dependent strategies have failed either as the result of inadequate safety testing in laboratory animals, or due to marked, and unexpected rates of non-compliance. Thus to have an actual impact on the HIV epidemic, an optimum prevention strategy must be safe, non-toxic, inexpensive, and free from the possibility of promoting the emergence of resistant strains. It also must be deliverable in a manner in which compliance can be assured. The most promising method of prevention remains an intravaginal ring that can be inserted once every three months and that provides consistent, sustained delivery of effective concentrations of antiviral drugs incapable of promoting HIV resistance. Further, the drug must be inexpensive to produce, highly stable at ambient temperatures for months, and safe with prolonged exposure to mucosal tissues. Here we submit that the latest generation of an HIV-1 nucleocapsid protein (NCp7) inhibitor called SAMT-247, delivered in a novel intravaginal ring formulation with unparalleled release characteristics, fits all of these criteria. We will also test the promising integrase inhibitor dolutegravir (DTG) in combination with SAMT-247 for safety and efficacy in preventing vaginal transmission, as data suggests it is also is not subject to viral resistance. Here we will test the safety, efficacy, and duration of protection against multiple high dose vaginal SHIV challenges in a rigorous nonhuman primate model. We hypothesize a SAMT-247/DTG combination delivered in a novel vaginal ring formulation can provide safe and sustained protection against repetitive SHIV challenge SHIV for at least 90 days, which would be a remarkable advance in HIV prevention strategies.